Biosimilar FSH preparations- are they identical twins or just siblings?

Orvieto and Seifer Reproductive Biology and Endocrinology (2016) 14:32 DOI 10.1186/s12958-016-0167-8 EDITORIAL Open Access Biosimilar FSH preparations- are they identical twins or just siblings? Raoul Orvieto1,2* and David B. Seifer3 Abstract As patents expire on innovator products, there is increasing interest in developing biosimilar products globally. Biosimilars are not exact copies and are not considered generic versions of the reference product. They may differ in strength, purity and contain different composition of isoforms and/or various glycosylation profiles, with the consequent alterations in clinical efficacy or safety. Recently 2 new recombinant FSH preparations were introduced to clinical practice following randomized controlled, phase 3 clinical trials. Both, Bemfola and Ovaleap® were referred to the FSH innovator product Gonal-f™ (Follitropin alpha), and were found to yield an equivalent number of oocytes (primary end-point), following a long GnRH agonist suppressive protocol in “ideal” patients, i.e., young, normal responders. However, a closer look at these RCTs reveals a non-significant 4 % difference in clinical and ongoing pregnancy rates, in favor of Gonal f over the biosimilar products, accompanied by half the incidence of OHSS (2.9 vs 5. 2 %, respectively). These studies were underpowered with reference to pregnancy rates, Thus, we believe that further comparative studies are needed in additional patient populations, e.g.,older,, poor responders, patients with repeated IVF failures and/or polycystic ovary syndrome, before the universal implementation of biosimilar products for clinical use. Biosimilars are actually a regulatory synonym, facilitating a fast track introduction of a FSH preparation to the COH armamentarium. We therefore recommend against interchanging or substituting innovator and biosimilar agents in clinical practice, and believe that the decision whether to use an innovator or a biosimilar product, should be reserved to the discretion of the treating physician. Furthermore, we believe the time has come that the measurement of the biological activity of FSH in humans should require other methods rather than the Steelman-Pohley assay, such as the determination of dose–response curves in defined populations of women with well-defined outcomes during COH in preparation for ART. Introduction As patents expire on innovator products, there is increasing interest in developing biosimilar products globally. The FDA describes biosimilars as biologic products that are “highly similar to the reference product not with-standing minor differences in clinically inactive components and that there are no clinically meaningful differences between the biologic product and the reference product in terms of safety, purity, and potency of the product” [1]. This definition makes it clear that biosimilars are not identical molecules or “generics” for biologic agents. They may still differ in strength, purity and contain different * Correspondence: 1 Department of Obstetrics and Gynecology, Infertility and IVF Unit, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan 52621, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Full list of author information is available at the end of the article composition of isoforms and/or various glycosylation profiles, with consequent alterations in clinical efficacy or safety [2, 3]. Therefore, the manufacturer of the biosimilar product is required to conduct phase III randomized controlled trials (RCT) aiming to demonstrate that those changes do not adversely affect the identity, purity,or potency of the potentially approved biologic product [4]. Notwithstanding, most health organizations do not consider biosimilar to be interchangeable with innovator product and recommend against substituting innovator and biosimilar agents in clinical practice. FSH has served for decades as the active component in different pharmaceutical preparations for treatment of infertility, e.g., to induce ovulation in oligo-anovulatory patients or to stimulate the development and maturation of a large number of follicles in patients undergoing controlled ovarian hyperstimulation (COH) for in vitro © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Orvieto and Seifer Reproductive Biology and Endocrinology (2016) 14:32 fertilization (IVF). While urinary FSH (uFSH) was used as the active material of the early pharmaceutical preparations used, recombinant FSH (rFSH) preparations produced in Chinese hamster ovary (CHO) cells, or human cell lines have become available later on. FSH isoforms It is well known that not only the levels of the FSH change during the different menstrual phases but also the composition of its different FSH isoforms. While Padmanabhan et al. [5] demonstrated that the rate of acidic isoforms in the serum is the lowest during the preovulatory and ovulatory phase; Ulloa-Aguirre et al. [6] found that the basic isoforms are secreted before ovulation. Zambrano et al. [7] have demonstrated that the proportion of the acidic isoform is higher during the early to mid-follicular phase compared to the preovulatory phase. When FSH activity is measured in vitro, acidic isoforms of FSH have a lower activity than the more basic isoforms. In contrast, when the activity is measured in vivo, the acidic isoforms of FSH have a higher activity than the basic isoforms of the same preparation thus, reflecting higher affinity and efficacy of the basic isoforms, with shorter half-life in vivo. Measurement of FSH preparations activity The activity of the FSH preparations can be measured in vitro or in vivo. Measurement of FSH activity in vitro can be performed by testing the efficiency of the binding of FSH to the membrane receptor, or by measuring the ability of FSH to stimulate enzymes or secondary messengers within target cells in culture. Measurement of the biological activity in vivo can be performed in animals and in humans. Since the 1950s, the most common and standard model for measuring the biological activity of FSH preparations in animals is the Steelman-Pohley assay, which is performed in two groups of immature female rats with low endogenous FSH level and is based on measuring ovary mass augmentation [8]. The activity of FSH preparations is influenced by the clearance rate of the hormone, which depends on the metabolism of different living organis (...truncated)